In this proposal we describe projects that aim to determine the mechanism by which mutations in the tau gene cause the neurodegeneration associated with Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). In addition we aim to examine the role of Tau in neurodegeneration in other diseases including Progressive supranuclear Palsy (PSP), Alzheimer's Disease, Pick's Disease and Cortico-basal degeneration (CBD). The PI's team reported the identification of missence and splice site mutations in tau, associated with FTDP-17 in the journal "Nature" in June of this year. The Projects are as follows: The Genetics of FTD and Tauopathies. This project will use genetic analysis to examine the possible association of variation in the tau gene with PSP, Pick's disease and CBD. In addition this project aims to identify the gene on chromosome 3 that is also linked with FTD. Mutations at this locus generate a phenotype that is almost indistinguishable from FTD-17 and thus it is important to identify this gene and determine its relationship, if any, with tau. Pathobiology of neurodegenerative disorders linked to mutations in the tau gene. The location of the missence mutations in the tau gene suggests that these likely affect the ability of Tau to bind microtubules. This project will examine this hypothesis using in vitro tubulin binding assays and will also study the effect of the mutations on the polymerization of Tau into fibrils. In addition this project will examine the effect of mutant Tau in transfected cells and will analyze the Tau from the brains of transgenic mice generated in projects 3 and 4. Analysis of the Role of 3 and 4 Repeat Tau in vitro and in vivo. This project will initially utilize in vitro splicing assays to determine the regulation of exon10 alternative splicing that is disrupted by the FTDP-17 splice site mutations. Subsequent studies that will performed in vitro, in transfected cells, and in vivo, in gene targeted mice, will examine the differing roles of 4 repeat and 3 repeat Tau in neuronal function. In addition the gene targeted tau mice will be used to test the hypothesis that the ratio of Tau4 and 3 repeat isoforms influences the toxicity of Abeta in vivo. Transgenic Modeling of Tauopathy. This project will utilize transgenic animals to model the effect of the Tau missence mutations in vivo. The brains of animals expressing wild type and mutant Tau cDNA constructs will be examined will be examined for the neurofibrillary tangles and neurodegeneration that are associated with FTDP-17. In addition animals expressing Human genomic tau constructs will be studied to see the effect of expressing Human Tau isoforms on Abeta sensitivity. These projects will operate around a Neuropathology Core whose broad goal will be to provide detailed morphological characterization of brains from Human patients and animal models that are derived from the research projects.